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Splenic nerves NE-β2AR axis exacerbate septic acute kidney injury via modulating neutrophilic immunosuppression [scRNA-seq]

ABSTRACT: Sepsis is characterized by chronic inflammation and immunosuppression, two immune states that hinder effective infection control and significantly contribute to renal pathological damage. Recent studies have underscored the crucial role of splenic neuroimmune interactions in immune response regulation. However, the precise mechanisms and functions of splenic nerve regulation of splenic immune responses in sepsis-associated acute kidney injury (SA-AKI) remain obscure. Our research suggests that preemptive Splenic Denervation in mice can mitigate sepsis-induced renal injury, while local norepinephrine injection into the spleen exacerbates sepsis-induced kidney damage in the cecal ligation and puncture (CLP) mouse model. Targeted blockade of splenic β2-adrenergic receptor signaling leads to increased survival rates and diminished renal damage in the mice treated with CLP. Subsequent experiments involving local splenic administration of Gr-1 antibodies and myeloid cell-specific conditional knockout of Adrb2 in mice validate that during sepsis, NE/β2-AR signaling can impact splenic neutrophils, fostering the progression of acute sepsis. Mechanistic inquiries reveal that splenic Adrb2 signaling boosts neutrophil PGE2 signaling through the cAMP pathway, promoting Th1 activation, diminishing local bacterial infections, and ameliorating SA-AKI. Furthermore, Blocking ADRB2 or PGE2 synthesizing signal significantly modulates the immunosuppression effect of neutrophils, promoting anti-bacterial Th1 immune response. These studies elucidate the role of splenic NE-ADRB2 signaling in regulating neutrophil immunosuppressive functions, thereby influencing the advancement of sepsis and renal tissue damage.

ORGANISM(S): Mus musculus

PROVIDER: GSE289831 | GEO | 2026/02/17

REPOSITORIES: GEO

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Project description:Sepsis-associated acute kidney injury (SA-AKI) is a critical condition characterized by high morbidity and mortality rates, particularly in intensive care settings. This study focuses on RP105, a pattern recognition receptor, exploring its role in moderating the mechanisms of oxidative stress and ferroptosis during SA-AKI, offering insights into its potential as a therapeutic target. SA-AKI model was established using RP105 knockout (KO) and wild-type (WT) mice through cecal ligation and puncture (CLP). Comprehensive evaluations included the assessment of ferroptosis markers and the expression levels of pro-inflammatory cytokines. RP105 expression was markedly reduced in the kidneys following CLP induction, correlating with worsened renal outcomes. Compared to the Sham group, RP105-/- mice displayed heightened renal damage, increased levels of oxidative stress markers, and enhanced lipid peroxidation. Notably, the deficiency of RP105 led to increased macrophage infiltration and a shift towards pro-inflammatory phenotypes, which further potentiated ferroptosis and exacerbated renal tissue damage. By influencing macrophage behavior and mitigating inflammatory responses. RP105 deficiency exacerbates macrophage-induced inflammation, oxidative stress, and ferroptosis, forming a vicious cycle that leads to more severe renal injury. These findings underscore the pivotal role of RP105 in mitigating oxidative stress and suppressing ferroptosis in the context of SA-AKI through regulation of the HO-1/SLC7A11/GPX4 axis. By preventing macrophage polarization toward a pro-inflammatory phenotype, RP105 alleviates inflammatory responses and tissue damage, highlighting its potential as a therapeutic target. In contrast, RP105 deficiency exacerbates macrophage-driven inflammation, oxidative stress, and ferroptosis, creating a vicious cycle that worsens kidney injury. Thus, RP105 emerges as a promising therapeutic candidate for mitigating sepsis-induced renal damage.

Project description:Background: We hypothesized that spleen microarray gene expression profiles analyzed with contemporary pathway analysis software would provide molecular pathways of interest and target genes that might help explain the affect of bcl-2 on improving survival during sepsis. Methods: Two mouse models of sepsis, cecal ligation and puncture and tracheal instillation of Pseudomonas aeruginosa, were tested in both wild-type mice and mice that overexpress bcl-2. Whole spleens were obtained 6 hours after septic injury. DNA microarray transcriptional profiles were obtained using the Affymetrix 430A GeneChip, containing 22,690 elements. Ingenuity Pathway Analysis software was used to construct hypothetical transcriptional networks that changed in response to sepsis and expression of the bcl-2 transgene. Results: A conservative approach was used wherein only changes induced by both abdominal and pulmonary sepsis were studied. At 6 hours, sepsis induced alterations in the abundance of hundreds of spleen genes, including a number of proinflammatory mediators (e.g., IL-6). These sepsis-induced alterations were blocked by expression of the bcl-2 transgene. Network analysis implicated a number of bcl-2-related apoptosis genes, including bcl2L11 (bim), bcl-2L2 (bcl-w), bmf, and mcl-1. Sepsis in bcl-2 transgenic animals resulted in alteration of RNA abundance for only a single gene, ceacam1. Conclusion: These findings are consistent with sepsis-induced alterations in the balance of pro- and anti-apoptotic transcriptional networks. In addition, our data suggest that the ability of bcl-2 overexpression to improve survival in sepsis in this model is related in part to prevention of sepsis-induced alterations in spleen transcriptional responses. Experiment Overall Design: To determine the splenic response in these lethal models of CLP and Pseudomonas pneumonia, microarray analysis was performed on each spleen harvested from wild-type animals 6 hours after CLP or tracheal instillation of bacteria. The responses of the CLP or Pseudomonas spleens were compared concurrently to those of the wild-type controls, sham laparotomy and tracheal instillation of saline, respectively. This study was repeated in animals overexpressing bcl-2. Thus, the splenocyte effect of sepsis secondary to CLP (n=6) or Pseudomonas pneumonia (n=5) could be determined compared to their controls (n=6 and 5, respectively), and the effect of bcl-2 overexpression in turn also could be determined in both CLP (n=5) and pneumonia models (n=5) compared to controls (n=5 and 5, respectively).

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Splenic nerves NE-β2AR axis exacerbate septic acute kidney injury via modulating neutrophilic immunosuppression [scRNA-seq]

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